CN1767078B - Preparation of radium-223, physically accepted preparation and kit - Google Patents
Preparation of radium-223, physically accepted preparation and kit Download PDFInfo
- Publication number
- CN1767078B CN1767078B CN2004100749238A CN200410074923A CN1767078B CN 1767078 B CN1767078 B CN 1767078B CN 2004100749238 A CN2004100749238 A CN 2004100749238A CN 200410074923 A CN200410074923 A CN 200410074923A CN 1767078 B CN1767078 B CN 1767078B
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- China
- Prior art keywords
- bone
- preparation
- radium
- acid
- radiation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- HCWPIIXVSYCSAN-OIOBTWANSA-N radium-223 Chemical compound [223Ra] HCWPIIXVSYCSAN-OIOBTWANSA-N 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 229960005562 radium-223 Drugs 0.000 title abstract description 25
- -1 alkaline earth metal cation Chemical class 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 8
- 150000001735 carboxylic acids Chemical class 0.000 claims description 8
- 239000000084 colloidal system Substances 0.000 claims description 8
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- 230000008021 deposition Effects 0.000 claims description 6
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- 239000012752 auxiliary agent Substances 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 125000002091 cationic group Chemical group 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 239000001630 malic acid Substances 0.000 claims description 3
- 235000011090 malic acid Nutrition 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 claims description 3
- 229910052712 strontium Inorganic materials 0.000 claims description 3
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims description 3
- 229940095064 tartrate Drugs 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 210000000988 bone and bone Anatomy 0.000 abstract description 73
- 238000000034 method Methods 0.000 abstract description 32
- 238000011282 treatment Methods 0.000 abstract description 19
- 210000004872 soft tissue Anatomy 0.000 abstract description 15
- 206010028980 Neoplasm Diseases 0.000 abstract description 11
- 230000008569 process Effects 0.000 abstract description 3
- 208000018084 Bone neoplasm Diseases 0.000 abstract 1
- 230000005855 radiation Effects 0.000 description 27
- 230000002285 radioactive effect Effects 0.000 description 24
- 239000007788 liquid Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 20
- 201000010099 disease Diseases 0.000 description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000002245 particle Substances 0.000 description 15
- 230000017105 transposition Effects 0.000 description 14
- 239000011347 resin Substances 0.000 description 13
- 229920005989 resin Polymers 0.000 description 13
- 239000000523 sample Substances 0.000 description 12
- 210000001519 tissue Anatomy 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 10
- 229910052705 radium Inorganic materials 0.000 description 10
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 10
- 238000000605 extraction Methods 0.000 description 9
- SYUHGPGVQRZVTB-UHFFFAOYSA-N radon atom Chemical compound [Rn] SYUHGPGVQRZVTB-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 229910052704 radon Inorganic materials 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 229910052500 inorganic mineral Inorganic materials 0.000 description 7
- 210000003734 kidney Anatomy 0.000 description 7
- 239000011707 mineral Substances 0.000 description 7
- 150000003009 phosphonic acids Chemical class 0.000 description 7
- 239000012217 radiopharmaceutical Substances 0.000 description 7
- 229940121896 radiopharmaceutical Drugs 0.000 description 7
- 230000002799 radiopharmaceutical effect Effects 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 230000003211 malignant effect Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- HCWPIIXVSYCSAN-YPZZEJLDSA-N radium-224 Chemical compound [224Ra] HCWPIIXVSYCSAN-YPZZEJLDSA-N 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 206010033799 Paralysis Diseases 0.000 description 5
- HCWPIIXVSYCSAN-IGMARMGPSA-N Radium-226 Chemical compound [226Ra] HCWPIIXVSYCSAN-IGMARMGPSA-N 0.000 description 5
- 230000005250 beta ray Effects 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- SYUHGPGVQRZVTB-OIOBTWANSA-N radon-219 atom Chemical compound [219Rn] SYUHGPGVQRZVTB-OIOBTWANSA-N 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- 210000000689 upper leg Anatomy 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- 206010060862 Prostate cancer Diseases 0.000 description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 4
- 230000002308 calcification Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- 230000000505 pernicious effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 210000000952 spleen Anatomy 0.000 description 4
- 239000012086 standard solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 229940122361 Bisphosphonate Drugs 0.000 description 3
- JCXGWMGPZLAOME-AKLPVKDBSA-N bismuth-212 Chemical compound [212Bi] JCXGWMGPZLAOME-AKLPVKDBSA-N 0.000 description 3
- 150000004663 bisphosphonates Chemical class 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 210000002805 bone matrix Anatomy 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- NFDRPXJGHKJRLJ-UHFFFAOYSA-N edtmp Chemical compound OP(O)(=O)CN(CP(O)(O)=O)CCN(CP(O)(O)=O)CP(O)(O)=O NFDRPXJGHKJRLJ-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- NDJKXXJCMXVBJW-UHFFFAOYSA-N heptadecane Chemical compound CCCCCCCCCCCCCCCCC NDJKXXJCMXVBJW-UHFFFAOYSA-N 0.000 description 3
- 238000001794 hormone therapy Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000000116 mitigating effect Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PSVQKOKKLWHNRP-UHFFFAOYSA-N 3-ethylheptane Chemical compound CCCCC(CC)CC PSVQKOKKLWHNRP-UHFFFAOYSA-N 0.000 description 2
- 229940120146 EDTMP Drugs 0.000 description 2
- WVYCUPGXDCILQL-UHFFFAOYSA-N P(O)(O)=O.P(O)(O)=O.C Chemical class P(O)(O)=O.P(O)(O)=O.C WVYCUPGXDCILQL-UHFFFAOYSA-N 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910052768 actinide Inorganic materials 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- RYXHOMYVWAEKHL-OUBTZVSYSA-N astatine-211 Chemical compound [211At] RYXHOMYVWAEKHL-OUBTZVSYSA-N 0.000 description 2
- JCXGWMGPZLAOME-NJFSPNSNSA-N bismuth-211 Chemical compound [211Bi] JCXGWMGPZLAOME-NJFSPNSNSA-N 0.000 description 2
- 201000001531 bladder carcinoma Diseases 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 150000001669 calcium Chemical class 0.000 description 2
- 239000012539 chromatography resin Substances 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000009849 deactivation Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- WABPQHHGFIMREM-RNFDNDRNSA-N lead-211 Chemical compound [211Pb] WABPQHHGFIMREM-RNFDNDRNSA-N 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 239000011859 microparticle Substances 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003608 radiolysis reaction Methods 0.000 description 2
- SYUHGPGVQRZVTB-YPZZEJLDSA-N radon-220 atom Chemical compound [220Rn] SYUHGPGVQRZVTB-YPZZEJLDSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000003352 sequestering agent Substances 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical group [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 229940006509 strontium-89 Drugs 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 229940127048 Metastron Drugs 0.000 description 1
- 206010027926 Monoplegia Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006045 Spondylarthropathies Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- RCXMQNIDOFXYDO-UHFFFAOYSA-N [4,7,10-tris(phosphonomethyl)-1,4,7,10-tetrazacyclododec-1-yl]methylphosphonic acid Chemical compound OP(O)(=O)CN1CCN(CP(O)(O)=O)CCN(CP(O)(O)=O)CCN(CP(O)(O)=O)CC1 RCXMQNIDOFXYDO-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001255 actinides Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 230000005262 alpha decay Effects 0.000 description 1
- BSJGASKRWFKGMV-UHFFFAOYSA-L ammonia dichloroplatinum(2+) Chemical compound N.N.Cl[Pt+2]Cl BSJGASKRWFKGMV-UHFFFAOYSA-L 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- JCXGWMGPZLAOME-RNFDNDRNSA-N bismuth-213 Chemical compound [213Bi] JCXGWMGPZLAOME-RNFDNDRNSA-N 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 238000004980 dosimetry Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000011347 external beam therapy Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229910052732 germanium Inorganic materials 0.000 description 1
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 239000007925 intracardiac injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000008798 osteoma Diseases 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001915 proofreading effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005258 radioactive decay Effects 0.000 description 1
- 238000011362 radionuclide therapy Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 150000003255 radium Chemical class 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 230000005477 standard model Effects 0.000 description 1
- CIOAGBVUUVVLOB-OUBTZVSYSA-N strontium-89 Chemical compound [89Sr] CIOAGBVUUVVLOB-OUBTZVSYSA-N 0.000 description 1
- AHBGXTDRMVNFER-FCHARDOESA-L strontium-89(2+);dichloride Chemical compound [Cl-].[Cl-].[89Sr+2] AHBGXTDRMVNFER-FCHARDOESA-L 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1282—Devices used in vivo and carrying the radioactive therapeutic or diagnostic agent, therapeutic or in vivo diagnostic kits, stents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Dispersion Chemistry (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Oncology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Biological Depolymerization Polymers (AREA)
- Materials For Medical Uses (AREA)
- Compounds Of Unknown Constitution (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
- Radiation-Therapy Devices (AREA)
Abstract
Processes for the preparation, prepared solutions, and the use of radium-223 for the treatment of calcified tumors, bone tumors, treatment of bones, bone surfaces and soft tissues are described.
Description
The application is to be that Dec 17, application number in 1999 are 99816102.0, exercise question is divided an application for " radium-223 is used for treating the purposes of the medicine of the disease that influences bone in preparation " the applying date.
The present invention relates to preparation and use " calcium analog " alkaline earth radioactive nuclide radium-223 to be used to aim at for example bone and comprising of calcified tissue
223Acceptable solution on the physiology of Ra.
Use radioactive nuclide to be used for alleviating pain and/or treatment cancer on the biomedicine, the prophylactic treatment that comprises bone surface was based on beta-ray radiator and conversion electron radiation body in the past to slow down/the undiscovered transfer of deactivation.
Quite the cancer patient of number percent receives the influence that bone shifts.The patient that as many as 85% suffers from advanced lung cancer, prostate cancer and breast cancer is developed transfer (Garret, 1993 of skeletonization; People such as Nielsen, 1991).For example hormone therapy of the treatment of having established, chemotherapy and external radiation therapy usually cause temporary transient reaction, but final most of osteocarcinoma patients experience recurrence (Kanis, 1995).Therefore strongly need new methods of treatment to ease the pain and the development of the tumour that slows down.The radioactive isotope of aiming at bone has been included in the clinical testing that is used for treating osteocarcinoma (people such as De Klerk, 1992, people such as Fossa, 1992, people such as Lee, 1996, Silberstein, 1996).These radiopharmaceutical are radiated body (Atkins, 1998) based on beta particle, recently also based on conversion electron radiation body people such as (, 1995) Atkins.In these compounds of food and drug administration's approval, strontium-89 (Metastron is arranged up to now
TM) and
153Sm EDTMP (Lexidronam
TM).The strontium-89 compound only can not be used for oncotherapy to be enough to lenitive amount medication, because before can reaching effective antitumour therapeutic dose degree, significant myelotoxicity (Silberman, 1996) will take place.
Recently, inventor writes book people such as (, 1999) Larsen, wherein shows that through dosimetry α-radiation body is more favourable than β radiation body as bone seeking material.Promptly when radioactive source was positioned at bone surface, more short-range a-radiation body caused less marrow radiation.In this research, two α-radiation bisphosphonates bone-seeking agent is compared with two β-radiation compounds with similar chemical constitution and bone affinity.Dosimetric calculating shows that in mouse, α-radiation body is compared bone surface with beta-ray radiator higher 3 times than about with marrow dosage.This show α-radiation bone-seeking agent perhaps than radiation β particle-and/or the electron radiation compound have more advantage because radiation dose can be concentrated on the bone surface more doughtily.Because short-half-life (t
1/2=7.2h) and because its production is limited to the whole world only minority is local, and astatine-211 still can not obtain in large-scale market at present.
Except that astatine-211, have only the radioactive isotope of minority radiation a-particle to be considered at present to can be used in the biomedical applications people such as (, 1997) Feinendegen.Plumbous-212/ bismuth-212 system had been used to prepare bone-seeking agent in the past.With ethylenediamine-four (methylene phosphonic acid) (EDTMP) or 1,4,7,10-tetraazacyclododecanand-1,4,7, the bismuth-212 that 10-four (methylene phosphonic acid) (DOTMP) cooperates has shown significant bone affinity.But because the short-half-life (t of bismuth-212
1/2=60.6min), the radiation of normal tissues is with quite a lot of (people such as Hassfjell, 1994,1997) in the radiopharmaceutic absorption stage.Be considered as the α-radiation bismuth isotope bismuth-213 (t of biomedical applications with another
1/2=46min) to compare this will be more remarkable.Plumbous-212 (t of beta-ray radiator have been attempted using
1/2=10.6h) conduct
212Generator in the body of Bi.Yet, observe remarkable transposition people such as (, 1997) Hassfjell of the a-radiation body that the high kidney of influence gathers.Other α-radiation radioactive isotopes that possibly be used for biomedical applications are radium isotope 224 and 226.11 bunches of earth alkali metal as other are the same, and the radium of kation state is natural bone-seeking agent.
Radium isotope 224 and 226 had been studied in the past, in part because their bone affinity (people such as Loyd, 1982,1991; People such as Muggenburg, 1996, Tiller, 1971; People such as Raabe, 1993; Rundo, 1978).Since its long half-lift (1600) with and rare gas radon-222 daughter (t
1/2=3.8 days), radium-226 is not considered and can be used for the radio nuclide therapy of target.Because its chemical property, radon is an inertia for chemical bonding under the condition in vivo.When it produces when parent nucleus decays therefore transposition in vivo promptly (Rundo, 1978).The radon that sucks mainly is dissolved in body fluid and the fat and mainly in body, removes (Rundo, 1978) through exhaling.In the experiment of using the bone sample, Lloyd and Bruenger (1991) have reported after radium-226 is delivered medicine to dog, and the radon of 89.5-94.25%-222 is overflowed from bone.As if opposite with radium-226, Radium-224 has the half life period (t that is well suited for biomedical applications
1/2=3.64 days).
224Ra medically is being used for many years with treatment ankylosing spondylitis (Delikan, 1978).Regrettably, also there is the daughter isotope of the Radium-224 of remarkable part from bone, to overflow, probably mainly due to radon-220 (t
1/2Be 55.6s) daughter (people such as Lloyd, 1982; People such as Miiller, 1971; Rundo, 1978).
Therefore from previous research, know and work as radium isotope
224Ra with
226When Ra was attached in the bone, significant transposition took place in their radon daughter, and this can partly explain the known carcinogenic effect of these two radium isotopes at least.This possibly be why clinically α-radiation body is not detected a radiopharmaceutic reason by assessment as the bone of treatment osteocarcinoma.
The object of the present invention is to provide the bone that can be used as medicament to detect radioactive nuclide, show from the not transposition significantly after it is attached in the bone of the radioactive decay product of its transformation (effective after administration 3 days at least).
Remarkable and the somewhat unexpected discovery of the inventor is according to what locate in the bone
223The transposition of few radon daughter other radioactive nuclide of decay chain (and from) has taken place in Ra.Therefore,
223Ra series can be used for shining bone surface, and has no the transposition (comprise and diffuse to marrow) of significant radioactive nuclide.Radium-223 more should be suitable as the radiopharmaceutical that bone is detected in addition, because its half life period (11.4 days) approximately is
224Three times of Ra, this made before decay takes place and deeper is attached in the matrix of bone surface.Equally, the more important thing is perhaps that radon daughter radon-219 has the short half life period (3.9 seconds), it should reduce transposition as a result in the radon stage or as the radon stage.
223Three in four alpha particles that radiate in Ra and the daughter nuclide decay process directly exist
223After changing in quality, radiates Ra people such as (, 1981) Seelman-Eggebert immediately, promptly as existing
223Three kinds of transformations at Ra back initial stage, 3.9 seconds
219The Rn alpha-decay is (table 1) with the longest half life period.
223Last α-radiation body in the Ra chain,
211Bi (t
1/2=2.15 minutes) follow the decay (t of beta-ray radiator lead-211
1/2=36.1 minutes), therefore perhaps show some transpositions.Yet, if precursor plumbous-211 is trapped within the bone matrix,
223Last alpha particle in the Ra series also possibly be sent to the bone surface zone.Alpha particle has high LET (height-LET) radiation that is to say for mammalian cell to have cytotoxicity (Hall, 1994 terrifically in addition; People such as Ritter, 1977).The radiation source that is positioned at the radiation alpha particle in the target tissue can be sent to less target area with radiation, therefore compares the radiation that has reduced normal tissues with beta-ray radiator.
The invention provides
(1) preparation is used for the method for radium-223 of biomedical applications, it is characterized in that parent nuclide is loaded in containing on the generator pillar of the AC-resin on the inorganic matrix, or is included in the step of using the AC-resin in liquid/liquid extraction system.
(2) according to the method for item (1); It is characterized in that containing in the generator pillar the methane bisphosphonic acid derivatives on the silica substrate and in liquid/liquid extraction step one or more P, di-2-ethylhexylphosphine oxide phosphonate derivative or its combination of P ' two esterifications are used as consisting of phase-transferring agent.
(3) according to the method for item (2); It is characterized in that containing in the generator pillar P on silica substrate; The two phosphonic acids of P ' dioctylmethane and in liquid/liquid extraction step P, P ' dioctyl di-2-ethylhexylphosphine oxide phosphonic acids or P, the two phosphonic acids of P ' two (2-ethylhexyl) methane or its combination are used as consisting of phase-transferring agent.
(4) according to the method for claim (1)-(3); It is characterized in that obtaining after containing neutralization in the generator pillar mineral acid of their compatible salt solusions of physiology; Preferred nitric acid or hydrochloric acid, and in liquid/liquid extraction step, use the water that contains mineral acid, preferred nitric acid or hydrochloric acid.
(5) according to the method for claim (4), the concentration that it is characterized in that mineral acid in the said pillar is 0.01M-8M, preferred 0.1M-2M; More preferably 0.5M-1M; And the concentration of mineral acid is 0.01M-8M in liquid/liquid extraction, preferred 0.1M-2M, more preferably 0.8M-1.5M.
(6) be used for acceptable preparation on the physiology of vivo medicine-feeding; It is characterized in that on pharmacology the acceptable carrier and auxiliary agent; Comprise radium-223 salt of aiming at the bone dissolving; Wherein contain or do not contain single kation or several cationic combination as stablizing alkaline earth metal cation analog carrier, contain or do not contain a kind of reagent that prevention deposition and/or colloid produce.
(7), it is characterized in that being selected from magnesium, calcium and strontium as the kation of stablizing alkaline earth metal cation according to the preparation of item (6).
(8), it is characterized in that preventing precipitating and/or reagent that colloid produces is the combination of carboxylic acid or carboxylic acid according to the preparation of item (6)-(7).
(9), it is characterized in that carboxylic acid is selected from oxalic acid, oxaloacetic acid, tartrate, succinic acid, malic acid and malonic acid according to the preparation of claim (8).
(10), it is characterized in that said preparation is processed and be used for injection, transfusion or picked-up, or the formulation of its combination according to the preparation of item (4)-(6).
(11) radium-223 preparation is used to treat the bone of falling ill and the purposes with pharmaceutical active preparation of bone surface.
(12) according to the purposes of item (11); Wherein said preparation is used for the combined treatment with another therapeutic activity component, for example comprise bisphosphonate chemotherapy, operation, external beam irradiation, emit the radiopharmaceutic low-LET radiation and the hormone therapy of detecting bone.
(13) according to the purposes of item (11)-(12), the preparation that wherein contains radium-223 salt of the dissolving of aiming at bone is used for treatment and/or the alleviation about the non-pernicious and malignant disease of bone that receives diseases and/or soft tissue.
(14) according to the purposes of item (13), wherein malignant disease is selected from prostate cancer, breast cancer, kidney and carcinoma of urinary bladder, primary osteocarcinoma, lung cancer and Huppert's disease.
(15) be used to prevent or treat the method for the non-pernicious or malignant disease of the mammalian bone that receives diseases and soft tissue, it is characterized in that comprising that mammal administration to needs relaxes or the preparation according to item (6)-(10) of treatment effective dose.
(16), it is characterized in that to mammal administration prevention effective dose preparation according to the method for item (15).
(17) according to the method for (14)-(16), it is characterized in that mammal is dog or people.
(18) kit is characterized in that containing with good grounds (1)-(5) preparation
223Ra, stablize the kation of alkaline earth metal cation analog carrier and reagent, pharmaceutically acceptable carrier and the suitable administration device that produces according to the anti-deposition of item (8)-(9) and/or colloid according to the conduct of item (7).
The present invention relates to preparation and use " calcium analog " alkaline earth radioactive nuclide radium-223 to be used to aim at for example bone and comprising of calcified tissue
223Acceptable solution on the physiology of Ra.
In present patent application, the inventor has invented
223A kind of new purposes of Ra promptly is used to aim at the tissue of calcification as the radiopharmaceutical of α-radiation, for example bone surface and osteoma damage.According to the character of radioactive nuclide and be present in the embodiment that tests in the present patent application and show that radium-223 can be suitable as bone and detect radiopharmaceutical.For example, the present invention can be through dosage that transmit to concentrate to patient's bone surface as preventative treatment of cancer, and this patient probably has undiscovered small metastatic tumor at bone surface.Its potentiality purposes another example will be the bony site of treating pain according to the radiopharmaceutic mode that being used to of describing before being similar to relaxes radiation β particle and the electron radiation of bone pain.
Be positioned on the bone surface and/or the calcification tumour in radium-223 can transmit strong and the alpha particle height local dose with its daughter nuclide, its radiopharmaceutical with the radiation β particle of present use and/or electron radiation is compared has less marrow dosage.The disease of bone for example primary or metastatic osteocarcinoma can be used
223The Ra radiopharmaceutical therapy.
The present invention includes and use nucleic to combine as cation type and/or with sequestrant or to the carrier molecule that calcified tissue has an another kind of form of affinity.This also includes but are not limited to radium-223 and can be connected to the combining of sequestrant that calcified tissue is had the affinity molecule subsequently.This purpose be the alpha particle that uses radioactive isotope to produce cascade on bone surface and/or in the calcification tumour be used to relax by the caused pain of different disease and/or be used to prevent maybe be minimum skeletal diseases, and/or the treatment of the osteocarcinoma that also is used to confirm.Can use radioisotopic disease to include but are not limited to transfer and the primary osteocarcinoma and the Huppert's disease of the bone of prostate cancer, breast cancer, kidney and lung cancer.
Preparation radium-223 solution is used to aim at calcified tissue or is used for the bone surface irradiation.Following example shows
223Ra in bone, have high with optionally absorb, wherein few daughter nuclide is located again.This shows that bone surface can be sterilized and can enough this isotope irradiations be used for relaxing or treatment with the damage of deactivation with the cancer of cancer cell that shows the visible deposition of mirror and calcification.This compound is different from other radiopharmaceutical commonly used with bone affinity, because main dose groups is divided from alpha particle, it is compared with the evaporation of electron body with the β of frequent use has narrower range.Therefore the dosage that is sent to red marrow can reduce by enough this noval chemical compounds significantly, and promptly myelotoxicity possibly be lowered.It is following that radium-223 is different from previously used medical radionuclide Radium-224: (1)
223Ra has the half life period of remarkable length, influences bone and soft tissue ratio preferably, because significantly a large amount of this isotopes partly will be removed from this soft tissue before decay takes place.(2) when carry out bone synthetic in the long half life period also make radioactive nuclide be bonded to bone surface dearly, the reservation of daughter isotope that can transposition because the recoil of the diffusion of chemistry and nuclear possibly improve.(3) with from
224Ra's
220Rn compare from
223The short half life period of Ra
219Rn, guaranteed from
223The less transposition of daughter nuclide of Ra series.
223The mammal that Ra salt or derivatives thereof will be for example oral, subcutaneous through whole effectively medicine-feeding ways, intravenous, intra-arterial or percutaneous dosing need is the people for example.This reactive compound is preferably through injection or transfusion administration.
For example suspending liquid, solution, syrup or emulsion carry out oral through using tablet, capsule, pulvis or liquid form.When processing tablet, use traditional excipient (expicients), lubricant and bonding agent.When with the mode administration of liquid, use traditional liquid-carrier.When with injection or or during the mode administration of transfusion solution, carrier is preferably isotonic saline solution, wherein contain or do not contain stablize the reagent that the radium kation prevents radium salt or insoluble complex compound sediment.
Can use effective constituent of the present invention to be used to receive prevention, mitigation and the treatment of non-pernicious and malignant disease of bone and the soft tissue of diseases.Malignant disease is selected from prostate cancer, breast cancer, kidney and carcinoma of urinary bladder (uninary cancer), primary osteocarcinoma, lung cancer and Huppert's disease, and nonmalignant disease is selected from autoimmune disease for example rheumatoid arthritis, schleroderma and the spondyloarthropathy that influences joint and bone.
Be used for acceptable preparation on the physiology of vivo medicine-feeding according to the present invention; On pharmacology acceptable carrier and the auxiliary agent; Radium-223 salt that comprises dissolving; Wherein contain or do not contain single kation or several cationic combination,, contain or do not contain of the generation of a kind of reagent with prevention deposition and/or colloid as stablizing alkaline earth metal cation analog carrier.Can be selected from magnesium, calcium and strontium as the kation of stablizing alkaline earth metal cation.In addition, the reagent that prevention deposition and/or colloid produce is the combination of carboxylic acid or carboxylic acid, for example oxalic acid, oxaloacetic acid, tartrate, succinic acid, malic acid and malonic acid.Compound concentrations is usually less than individual LD50 dosage in the preparation, for example less than 20% LD50 dosage, therefore can change for different components.Give mammal for example during people's medication with single dose or multiple dose mode,
223The activity of Ra depends on type and approach and the basic state of an illness or the disease of administration, between about 50KBq-10MBq, changes.
Radium-223 is used to produce the pharmaceutical active preparation influences bone, bone surface and soft tissue with mitigation and treatment non-pernicious and malignant disease according to the present invention in addition.Said preparation with relax or remedially effective dose deliver medicine to mammal for example human or animal such as the dog that needs it.
The radium according to the present invention-223 can be used to combined treatment, wherein
223The Ra preparation combines with the treatment of following kind; The chemotherapy, operation, the external beam that comprise bisphosphonates shine, emit radiopharmaceutic low LET radiation and hormone therapy that bone is detected.
The present invention relates to kit in addition, comprise and producing according to the inventive method
223Reagent, pharmaceutically acceptable carrier and the suitable administration device that corresponding kation of alkaline earth metal cation analog carrier and prevention deposition and/or colloid produce stablized in Ra, conduct.
Describe the present invention in detail through embodiment hereinafter, it is used for restriction anything but as enclosing the described scope of the present invention of claim.
Table 1 has provided the physical characteristics (people such as Ekstrom, 1989) of radium-223 and daughter nuclide thereof.
223The decay of Ra and daughter thereof causes the emission of four alpha particles.The alpha particle of this cascade can transmit in large radiation dosage to the limited volume.Therefore compare with most of α-radiation body, radium-223 also has cytotoxicity people such as (, 1997) Howell of extreme.
Shown radium-223 and daughter disintegration thereof series (expression half life period and decay modes in the bracket) as follows:
223Ra (11.4d., α)=＞219Rn (3.9s., α)=＞215Po (1.8ms., α)=＞Pb (36,1min., B-)=＞
211Bi (2.15min., α)
207T1 (4,8min., B-)
207Pb (stable)
Table 1
223The radiation of Ra and daughter
*
| Nucleic | 223Ra | 219Rn | 215Po | 211Pb | 211Bi | 207T1 |
| α-energy | 5.64MeV | 6.75MeV | 7.39MeV | 6.55MeV | ||
| β-energy (maximum) | 0.47MeV | 0.47MeV | ||||
| The energy mark | 0.207 | 0.248 | 0.271 | ≤0.017 | 0.24 | ≤0.017 |
* data are from people such as Seelmann-Eggebert, 1981 with people such as Ekstr φ m, 1989
Total emitted energy of the whole relatively decay chain of #.
With
223The binding energy of the emitted radiation that Ra is relevant with the whole decay of daughter :～27.5MeV
With the energy of the form of alpha particle radiation partly:＞96%
With the energy of the form of beta particle radiation partly:＜3%
In decay process, also radiate some γ radiation and (amount to＜0,3MeV) and can be used for using isotopic quality and quantity in the γ Wave Spectrum decision sample.For example radium-223 has a characteristic γ peak (5.59% abundance) at 154.19keV, and radon-219 has a peak (6,6%) and bismuth-211 that a 351.0keV peak (12.8%) (people such as Ekstrom, 1989) is arranged at 401.78keV.These can be used for determining whether daughter isotope takes place heavily to distribute in vivo.
223Ra also has a 269.41keV peak, and abundance is 13.6%, but this distinguish in
219The abundance of Rn is 9.9% 271.23keV peak.
The existing preparation method who has described radium-223 (people such as Atcher, 1989; People such as Howell, 1997).Radium is a member in the natural radiation family, derives from U (t
1/2=7 * 10
8Y) warp
231Th (t
1/2=25.6y.) and the order
231Th-＞
231Pa (t
1/2=3.3 * 10
4Y.)-＞
227Ac (t
1/2=21.7y.)-＞
227Th (t
1/2=18.7d.)-＞
223Ra (11.4d.).People such as Atcher (1989) use cation exchange system (Bio-rad AG 50) from
227Ac generates
223Ra.People such as Howell (1997) use
226Ra (n, r)
227The Ra nuclear reaction generates
223Ra.
227Ra (t
1/2=42min) become apace
227Ac (t
1/2=21.77 years), its can through diverse ways from
226Separate in the Ra target thing.People such as Howell (1997) separate from target solution with chemical method
227Ac.Then
227Ac transfers to reservation with its daughter product
227In the anion-exchange column of Th, the parent and the daughter of this nucleic of wash-out simultaneously.Can from ion exchange column, go out by wash-out after ten days
223Ra.If through utilizing the generator principle to prepare clinical batch, perhaps the ion exchange column of using based on organic main chain is suboptimal, because radiolysis can prevent long-term comprehensive utilization people such as (, 1989) Atcher based on this type material radium generator.
Development of new material recently, and can buy on the market now, it can be used for the separation (the f-element is to the selectivity of alkaline earth element) of actinide radioactive nuclide.These are based on the silica microparticle of covalent bonding reactive group or doping reactive group.Can use this material preparation pillar to make that wash-out goes out some elements under the condition that can keep other elements.Also possibly use reactive group to be used for adopting the separating of wet/wet method extraction system of organic and water.
Embodiment
Prepared among the embodiment 1 below
223Ra.The present invention's preparation is used for biomedical applications
223The new method of Ra comprises inorganic matrix post and liquid/liquid system.The generator post or the said method that contain the methane bisphosphonic acid derivatives on inorganic matrix can comprise that also liquid/liquid extracts operation steps, wherein one or more P, and the di-2-ethylhexylphosphine oxide phosphonate derivative of P ' two esterifications is as consisting of phase-transferring agent.
The generator post contains the P on silica substrate in the method, and the two phosphonic acids of P ' dioctylmethane and liquid/liquid extract operation and is to use P, P ' dioctyl di-2-ethylhexylphosphine oxide phosphonic acids or P, and the two phosphonic acids of P ' two (2-ethylhexyl) methane or its combine as consisting of phase-transferring agent.Operation about the generator post is carried out through using the mineral acid that after neutralization, can access the solution of their compatible on physiology salt, preferred nitric acid or hydrochloric acid.The concentration of described mineral acid is within the 0.01-8M scope, more preferably between 0.1-2M, most preferably between 0.5-1M.The water that use contains mineral acid, preferred nitric acid or hydrochloric acid carries out liquid/liquid extraction step, and acid concentration is within the 0.01-8M scope, more preferably between 0.1-2M, most preferably between 0.8-1.5M.
Embodiment 1
Prepared in the past from 27 years through the chromatography resin that uses the selective extraction of f-element
231Separate in the Pa source (sample is by Univ Oslo Norway, department of chemistry, the radiochemistry group provides)
227Ac with
227Th.Purify
227Ac with
277Th is adsorbed on the chromatography resin of another kind of f-element selective extraction subsequently and is used as
223The cow of Ra.The latter material by people such as Wu (1997) be used for building based on
225Ac's
213The Bi generator.
Method: will be at 5M H with 1M HCl
2SO
4With in the 1M HF WS
23110 times of the diluted samples of Pa radioactive source (containing daughter).This solution is loaded in 3 millimeters of internal diameters and 70 millimeters of length and contains on the pillar of the TRU-resin (EiChroM industry, Darien, IL, the U.S.) that useful 1M HCl pre-equilibration crosses.
231Pa is retained on the pillar, and
227Ac,
227Th with
223Ra then part comes wash-out through pack into operation wash-out and part through washing pillars with 10 milliliters of other 1M HCl.The improved method of the column packing technique of after this, describing through people such as use Wu prepares
223Ra generator (1997).Preparation and handle 3x50 millimeter silica actinide resin pillar (EiChroM, Darien, IL in advance with 1M HCl; The U.S.), this pillar is by diameter P on the silica microparticle in the 20-50 mu m range, the two phosphonic acids (DIPEX of P ' dioctylmethane; EiChroMEiChroM industry; Darien, IL, the U.S.) form.From this pillar, removing only about half of resin then mixes with eluent from the TRU-resin column then.
To contain thereafter
227Ac,
227Th with
223The eluent of Ra is loaded in the pillar of 3 millimeters internal diameters and 50 millimeters long, and this pillar contains the actinide-resin (Ac-resin) on the 30-50 μ m silica (EiCroM industry, Darien IL, the U.S.).In brief, the method according to people such as Wu prepares this pillar.(1997)。After handling pillar in advance with 1M HCl, half the material is removed then and mixes with the eluent that comes comfortable preceding step.
After at room temperature mitigation was stirred 4 hours, the slurries that will contain radioactive nuclide were loaded in this pillar.At last, with 5 milliliters of these pillars of 1M HCl washing.Kept in this pillar
227Ac with
227Th, and
223Ra can use several milliliters of HCl or HNO
3Wash-out, its parent and grandmother's body radioactive nuclide have no significantly and spill.If desired, can add purification step subsequently, promptly pass through the 2nd AC-resin column wash-out simply
223Parent and the grandmother body nucleic of Ra eluent to remove any trace.
Contain
223The HCl solution of Ra can dilute in impact damper, aseptic filtration is used then after this manner.In addition, purifying
223Ra can be concentrated before using, and promptly contained resin for example in the pillar of AG 50W-X4-16 (Bio-Rad, Richmond, CA, the U.S.) through what HCl solution is loaded in 2 millimeters internal diameters and 25 millimeters long.Thereafter
223Ra can be through the 6M HNO of little volume
3Almost by wash-out quantitatively.Thereafter HNO
3Can be evaporated, residue can be dissolved in the solution again, subsequently by aseptic filtration.
Use with from EG & G Ortec (Oak Ridge; TN, U.S.) being used for the amplifier of γ liquid spectroscopy and germanium-detecting device that bias box combines and/or the Canberra (model 7,404 01 A) that combines with the EG & G Ortec that is used for the α Wave Spectrum carries out the measurement of radioactivity quality and quantity.
The result: in the TRU resin column,
231Pa is kept quantitatively, promptly compares this with daughter activity and spills less than 0.5% of detection limit.More than 90%
227Ac with
227Th is collected in the eluent from the TRU resin.For the AC-resin, experiment repeatedly is presented in the pillar (being also referred to as cow or generator) every 100kBq in initial several milliliters stripper solution
227Th generally produces 60-85 kBq
223Ra.With
223Ra compares
227Ac with
227Th spills through measuring less than (receiving the restriction of detectability) 4 * 10
-3%.Should be noted that described separation method also can with by
226The Ra warp
226Ra (n, γ)
227Ra-＞
227Ac generates
227Ac uses together.
Conclusion: described a group of methods and be used to prepare the high yield of guaranteeing to can be used for biological applications and highly purified
223Ra.Its difference be by
227The radioactivity level that the conventional preparation of Ac is relevant clinically
223Ra is easier.This method uses the generator pillar based on silica substrate to carry out people such as (, 1997) Wu, and the method for preexist comprises more ion exchange resin responsive to radiolysis that contain organic substrate people such as (, 1989) Atcher more.
Embodiment 2
Studied the bio distribution of the radium-223 of method preparation described in embodiment 1.
Method: with containing 9kBq
223The 150ul isotonic saline solution of Ra is the few male Balb/C mouse injection of children of 19-21 gram to body weight.Every group of 5 animals, after injection 6 hours and 3 days put to death each treated animal and dissect.The weight of measuring samples is used (A) and Scaler timer ST7 (NE technology company limited, Reading; Britain) well type NaI scintillation crystal (the Harshaw Chemie BV that combines; De Meern, Holland) digital device, (B) the Beckman LS 6500 (Fullerton of Beckman instrument company; CA, the U.S.) the counting sample.Use with from EG & G Ortec (Oak Ridge; TN, U.S.) germanium-detecting device (Canberra, the Meriden that combine of amplifier and bias box; CT, U.S.) relative abundance of research radioactive nuclide when parent/daughter is in balance in blood, liver, kidney and standard model.
The result: these bio distribution data are listed in the table 2.Data presentation is compared with soft tissue
223Ra is concentrated in bone selectively.And all soft tissue values reduce between after the injection 6 hours and 3 days, and the bone value increases in time.Ratio from 6 hours to 3 days femurs and blood is increased to 691 from 129.The highest retention that has measurement in the soft tissue that contains in the spleen, but the ratio of femur and spleen also is increased to 23.7 from 6.4 in time between back 6 hours and 3 days of injection.
The bio distribution of table 2 radium-223 in the Balb/C mouse is expressed as the ID % of every gram
| Tissue | 6 hours | 3 days |
| Femur | 25.86±1.99 | 34.55±7.87 |
| Blood | 0.20±0.23 | 0.05±0.10 |
| Kidney | 4.04±0.33 | 0.38±0.08 |
| Liver | 0.89±0.18 | 0.22±0.32 |
| Lung | 0.59±0.56 | 0.06±0.07 |
| Muscle | 0.72±0.39 | 0.30±0.16 |
| Heart | 0.10±0.10 | 0.06±0.07 |
| Brain | 0.04±0.01 | 0.12±0.12 |
| Spleen | 4.06±1.4 | 1.46±0.54 |
| Small intestine | 0.79±0.26 | 0.04±0.03 |
| Large intestine | 2.30±0.60 | 0.13±0.02 |
According to the γ Wave Spectrum, in bone and most soft tissue, do not observe by
211The significant difference that radium-223 that the Bi abundance is confirmed and daughter thereof distribute relatively.In 6 hours some spleens
211Bi:
223The ratio of Ra is compared average out to 54% with standard solution.On the other hand, in liver and kidney in the sample
211Bi:
223The Ra ratio on average is respectively 256 and 207% of standard.This is illustrated in some transpositions has taken place in the soft tissue.Compare in the soft tissue with the bone radioactivity of this nucleic
211The Bi radioactivity is general also very low.In the soft tissue
211Bi is perhaps from be present in soft tissue
223Ra produces.
Conclusion: by
223Ra and daughter obtain fabulous bone and normal tissues activity ratio, and this shows with this radioactive nuclide series aims at the significant potential of calcified tissue.
Embodiment 3
Whether can to occur the difference that radioactive isotope keeps between radium-223 and the bismuth-211 in the bone sample in order checking, to have studied bone and be in balance containing
223The γ spectral data of the standard solution that Ra and daughter activity are verified.
Method: directly carry out the γ Spectrum Analysis with germanium detecting device (Canberra, Meriden, CT, the U.S.) on the sample at mouse femur at this animal dead with after dissecting.Studied and be in balance
223The sample of the standard solution of Ra and daughter activity nucleic.Use 351.0keV (
211Bi) and 154.2keV (
223Ra) locate tangible γ peak.Locator index (LI) is defined as follows:
LI＝(B
Bi/S
Bi)/(B
Ra/S
Ra)
For example, B
Bi-
211The counting rate of Bi in bone; S
Ra-
223The standard meter digit rate of Ra
Use Student t-test data pillar to compare respectively with from five of standard solution and three samples from the γ wave spectrum of 6 hours groups and five samples organizing in 3 days.
Result: at the LI of 6 little time points value average out to 0.85 (P=0.059), at the LI value average out to 0.97 (P=0.749) of 3 days points.Yet, not remarkable with respect to the level difference of data set P=0.05.
Conclusion: even for representative
223The radioactive nuclide of the 4th transformation in Ra, the 211 Pb-disintegration series, the retention in the bone with
223Ra is similar.
Embodiment 4
In order to study
223The potential release of daughter isotope after Ra is absorbed in the bone, since the recoil or the diffusion process of nuclear, the femur of check back 6 hours killed five animals of injection and 3 days killed five animals.
Method: to make red marrow (spongious) zone in order shining, bone vertically to be rived, be cut into fractionlet thereafter less than 3 milligrams.Use centrifuge method with Dulbeccos PBS (Sigma-Aldrich CO.LTD., Irvine, Britain) washing sample thereafter.Remove supernatant liquor, mix (adding Insta-Gel11, Packard BioScience BV, Groningen, Holland) with scintillation solution, go up counting at scintillation counter (Beckman instrument company, Fullerton, CA, the U.S.) then.Double counting sample after one day.Proofreading and correct between twice measurement
223The difference of counting is used as the release of expression daughter nuclide from bone matrix after the Ra decay.
The result: killed animal has shown some radioactive releases from bone after 6 hours.Compare in washing process average 1.8% with the gross activity in the bone and be dissolved in PBS.When measuring cleansing solution once more after 12 hours, radioactivity only average out to bone sample 0.2%.But this shows the transposition degree that some daughter isotopes have taken place very little (be below about daughter isotope 2%).Do not show significant number with killed animal after the substrate in the cleansing solution is compared 3 days after the washing.This shows if transposition takes place, and then is lower than detection limit, estimates less than total bone radioactive 1%.
Conclusion:, show that the release (transposition) of daughter nuclide from bone matrix is lower for radium-223 series according to extractible radioactive segment from the bone sample of meticulous pulverizing.
Embodiment 5
After deliberation have an animal model (Engebraaten and Fodstad, 1999) that is similar to the transfering type of frequent observed experiment among the patient.In these models one form, be characterised in that in animal, as one man to have formed hind leg paralysis by intracardiac injection MT-1 cell in the exposed rat.Do not improve survival rate with chemotherapeutant neoplatin or the mould extract for treating of Ardelia (after the inoculated tumour cell seven days).Dissect and replace normal marrow and corrode the tumour cells of the part of spinal bone with the backbone demonstration of microscopic examination tumor-bearing animal is a large amount of.
Involving of bone makes it be suitable for proving the present invention in the model of above-mentioned research
223Ra shifts the potentiality of treatment to bone.
Method: in the exposed rat model of MT-1/, studied the treatment potentiality of radium-223, wherein given animal inoculation pvaccination 1 * 10 through as described, being expelled to left ventricle
6MT-1 people's breast cancer cell (Engebraaten and Fodstad, 1999).These animals develop into by the caused paralysis of growth of tumor in the backbone usually.The group of 4 and 5 animals is handled in the intravenous injection of the 200ul carrier solution through accepting not contain or to contain 10 kBq radium of the present invention-223 after seven days.
The result: the group of four animals of only handling with carrier solution suffers from the inoculated tumour cell after and receives paralysis and the execution (referring to 22,25 days) between 20-25 days that tumor growth influences in the backbone.Contain in acceptance
223In the group of five animals of Ra carrier solution; An animal was benumbed after 26 days, a paralysis after 40 days, a paralysis after 64 days; And the whole experiment in remaining two animals 90 days after the inoculated tumour cell interim survival when following the tracks of shows the sign of paralysis.
Conclusion:
223The Ra proof has significant antitumous effect in the animal that suffers from the skeleton transfer.
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Claims (5)
1. the acceptable preparation of physiology that is used for vivo medicine-feeding; It is characterized in that on pharmacology the acceptable carrier and auxiliary agent; Radium-223 salt that comprises dissolving; Wherein contain or do not contain single kation or several cationic combination as stablizing alkaline earth metal cation analog carrier, contain or do not contain a kind of reagent that prevention deposition and/or colloid produce.
2. according to the preparation of claim 1, it is characterized in that being selected from magnesium, calcium and strontium as the kation of stablizing alkaline earth metal cation.
3. according to the preparation of claim 1 or 2, it is characterized in that preventing precipitating and/or reagent that colloid produces is the combination of carboxylic acid or carboxylic acid.
4. according to the preparation of claim 3, it is characterized in that carboxylic acid is selected from oxalic acid, oxaloacetic acid, tartrate, succinic acid, malic acid and malonic acid.
5. according to the preparation of claim 1, it is characterized in that said preparation is processed and be used for injection, transfusion or picked-up, or the formulation of its combination.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993009816A1 (en) * | 1991-11-14 | 1993-05-27 | Battelle Memorial Institute | Method for diagnosing and treating cancer |
| US5809394A (en) * | 1996-12-13 | 1998-09-15 | Battelle Memorial Institute | Methods of separating short half-life radionuclides from a mixture of radionuclides |
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